PROJECT SUMMARY Radiation induced lymphopenia (RIL) is a common radiation-related toxicity that has been recognized for over a century but often ignored as clinically inconsequential. However, accumulating evidence has demonstrated strong association of high grade RIL (seen in 30-50% of patients) with poor prognosis. The pervasive role of radiotherapy in the curative management of solid tumors supports the need to develop mitigating strategies, particularly for patients with a high risk of developing grade 4 (G4) RIL. We have compelling evidence from both clinical and preclinical work that severe RIL impacts cancer control and therapy effectiveness, and methods to reduce RIL may improve treatment outcomes. To further develop these approaches for clinical translation, we have proposed 2 specific aims. In aim 1, we will build on our initial prediction model for G4 RIL and leverage our large database of esophageal cancer patients who have completed chemoradiation (CRT) to develop a better predictive model for G4 RIL so that we can rapidly and efficiently identify the highest risk patients for mitigating strategies. In aim 2, we will determine the feasibility and safety of raising the baseline lymphocyte levels by autologous lymphocyte infusion (ALI) prior to initiating CRT. Fundamentally, this research will allow us to develop the necessary computational tool capable of properly identifying patients at risk for developing severe RIL, and complete a small feasibility and safety study of using ALI as a way to raise the baseline pre-treatment lymphocyte levels so that the probability of developing G4 RIL could be possibly curtailed. By targeting the at-risk patients to receive RIL mitigating strategies, we will hopefully be able to improve the cancer outcomes of standard cancer therapies, and build on current innovative strategies of immunotherapy and radiation combinations.